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EP1184376A1 - Nouveaux derives carboxamide heterocycliques - Google Patents

Nouveaux derives carboxamide heterocycliques Download PDF

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Publication number
EP1184376A1
EP1184376A1 EP00935619A EP00935619A EP1184376A1 EP 1184376 A1 EP1184376 A1 EP 1184376A1 EP 00935619 A EP00935619 A EP 00935619A EP 00935619 A EP00935619 A EP 00935619A EP 1184376 A1 EP1184376 A1 EP 1184376A1
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EP
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Prior art keywords
lower alkyl
carboxamide
cis
substituent
compound
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EP00935619A
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German (de)
English (en)
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EP1184376A4 (fr
EP1184376B1 (fr
Inventor
Hiroyuki Yamanouchi Pharma. Co. Ltd. HISAMICHI
Souichirou Yamanouchi Pharma. Co. Ltd. KAWAZOE
Kazuhito Yamanouchi Pharma. Co. Ltd. TANABE
Atsushi Yamanouchi Pharma. Co. Ltd. ICHIKAWA
Akiko Yamanouchi Pharmaceutical Co. Ltd. ORITA
Takayuki Yamanouchi Pharma. Co. Ltd. SUZUKI
Kenichi Yamanouchi Pharmaceutical Co. Ltd. ONDA
Makoto Yamanouchi Pharma. Co. Ltd. TAKEUCHI
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Astellas Pharma Inc
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Yamanouchi Pharmaceutical Co Ltd
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Publication of EP1184376A4 publication Critical patent/EP1184376A4/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to a heterocyclecarboxamide derivative useful as a medicament, particularly a Syk inhibitor.
  • type I immediate type allergic reaction which plays a main role at allergic diseases as typified by bronchial asthma, allergic rhinitis or atopic dermatitis is initiated by the interaction between an extrinsic antigen such as pollen or house dust and immunoglobulin E (IgE) specific thereto.
  • IgE is captured on the cell surface of mast cell and basophile manifesting IgE receptor (Fc ⁇ RI) having a high affinity.
  • Fc ⁇ RI IgE receptor
  • the antigen binds thereto and cross-links the receptor, the cell is activated and inflammatory mediators such as histamine, serotonin and the like inducing anaphylaxis reaction are released from cytoplasmic secretory granules.
  • inflammatory mediators such as histamine, serotonin and the like inducing anaphylaxis reaction are released from cytoplasmic secretory granules.
  • cytokine which takes part in the progress of inflammatory reactions
  • Syk undergoes tyrosine phosphorylation by the action of Lyn after crosslinking of Fc ⁇ RI by an antigen, whereby the activity of the tyrosine kinase increases (Hutchcroft, J.E. et al., Proc. Natl. Acad. Sci. USA, 89:. 9107-9111 (1992)). It has been also shown that the activation of Syk are necessary for the degranulation and cytokine production acceleration induced by the activation of Fc ⁇ RI (Rivera, V. M. and Brugge, J. S., Mol. Cell. Biol., 15: 1582-1590 (1995)).
  • Syk is essential for a life-extending signal of eosinophiles mediated by GM-CSF receptor, because antisense oligonucleotide of Syk inhibits the eosinophile's life-extending action of GM-CSF (Yousefi, S. et al., J. Exp. Med., 183: 1407-1414 (1996)).
  • Syk takes part in allergic or inflammatory reaction through controlling the functions of mast cell, basophile, and eosinophile.
  • Syk is suggested to be concerned in various diseases as described below.
  • Syk is deeply concerned in the phosphatidylinositol metabolism and increase in the intracellular calcium concentration caused by the stimulation of B cell antigen receptor and thus plays an important role at the activation of B cells (Hutchcroft, J. E. et al., J. Biol. Chem., 267: 8613-8619 (1992) and Takata, M. et al., EMBO J., 13: 1341-1349 (1994)).
  • a Syk inhibitor may control the function of B cell and therefore is expected as an therapeutic agent for the diseases in which the antibody produced by B cell are concerned.
  • heterocyclecarboxamide derivatives having a substituted amino group the following compound is disclosed in Indian J. Chem., Sect. B, 16B(10), 932-933 (1978), the following compound in EP475206 and US5104877, and the following compound in Japanese Patent Laid-Open No. 94677/1974, but the action on Syk of these compounds is neither disclosed nor suggested.
  • a heterocyclecarboxamide derivative has a satisfactory Syk inhibitory activity and is useful as an agent for preventing, treating, or diagnosing diseases in which Syk takes part, and thereby have accomplished the invention.
  • the invention relates to a novel heterocyclecarboxamide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, and a medicament comprising the same as the active ingredient. (wherein the symbols in the formula have the following meanings.
  • the central heterocycle part represents any of the following formulae: and when Y-Z represents N(R 5 )-C(O), C(O)-N(R 5 ), N(R 5 )-N(R 5 ), or C(O)-C(O) in the formula, the central heterocycle part represents any of the following formulae.
  • a pharmaceutical composition particularly a Syk tyrosine kinase inhibitor comprising the above heterocyclecarboxamide derivative or a salt thereof.
  • lower means a linear or branched hydrocarbon chain having from 1 to 6 carbon atoms.
  • the "lower alkyl group” is preferably a lower alkyl group having from 1 to 4 carbon atoms, and more preferred is methyl, ethyl, or isopropyl group.
  • the "lower alkylene” is preferably a lower alkylene having from 1 to 4 carbon atoms, and particularly preferred is methylene, ethylene, or butylene.
  • halogen includes F, Cl, Br, and I.
  • lower alkyl substituted by halogen(s) is preferably fluoromethyl, trifluoromethyl, or trifluoroethyl group.
  • arylene means divalent groups formed by removing hydrogen atom at any position of "aryl group”, “heteroaryl group”, and “cycloalkyl group”, respectively.
  • the "aryl group” is preferably a monocyclic to tricyclic aryl group having from 6 to 14 carbon atoms, more preferably, a phenyl group or a naphthyl group. Also, the phenyl group may be condensed with a five- to eight-membered cycloalkyl ring to form, for example, an indanyl group or a 5,6,7,8-tetrahydronaphthyl group, which combines from the aromatic ring.
  • the "arylene” is preferably 1,2-phenylene or 1,4-phenylene.
  • the "cycloalkyl group” is preferably a cycloalkyl group having from 3 to 8 carbon atoms. More preferred as the "cycloalkylene” is cyclohexane-1,1-diyl, 1,2-cyclopentylene, 1,2-cyclohexylene, or 1,4-cyclohexylene. Also, the cycloalkyl group may be condensed with a benzene ring to form, for example, 1- or 2-indanyl or a 1,2,3,4-tetrahydronaphthyl group.
  • heteroaryl group is a five- to six-membered monocyclic heteroaryl group having from 1 to 4 hetero atoms selected from O, S and N, and is preferably pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, or thiazolyl group.
  • Substituents of the "lower alkylene which may have substituent(s)", "arylene which may have substituent(s)", “heteroarylene which may have substituent(s)”, “cycloalkylene which may have substituent(s)” and “aryl which may have substituent(s)” are not particularly limited so long as they can be used as substituents of these rings, but are preferably the substituents selected from the following group. One to four of these substituents may be present.
  • the "-NH 2 in a prodrug form” means any of the groups well known by those skilled in the art, which forms -NH 2 under physiological conditions.
  • groups well known by those skilled in the art which forms -NH 2 under physiological conditions.
  • a in the formula (I) is preferably a lower alkylene or cycloalkylene, more preferably ethylene or cyclohexylene.
  • R 3 is preferably -CO 2 H, -CO 2 -lower alkyl, -lower alkylene-CO 2 H, -lower alylene-CO 2 -lower alkyl, -NH 2 , -(NH 2 in a prodrug form), -lower alkylene-NH 2 , or -lower alkylene-(NH 2 in a prodrug form), further preferably -NH 2 , -(NH 2 in a prodrug form), -lower alkylene-NH 2 , or -lower alkylene-(NH 2 in a prodrug form) , more preferably -NH 2 or -(NH 2 in a prodrug form).
  • X is preferably NR 4 .
  • the compound of the invention may exist in the form of geometrical isomers or tautomers, and isolated forms or mixtures of these isomers are included in the invention.
  • the compound of the present invention may contain an asymmetric carbon atom in some cases, so that isomers based on the asymmetric carbon atom may exist. Mixtures or isolated forms of these optical isomers are included in the present invention.
  • the compound of the present invention sometimes forms an acid addition salt or, depending on the kinds of substituents, a salt with a base.
  • Such salts are pharmaceutically acceptable salts, and illustrative examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid and the like; salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum and the like or with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine and the like; ammonium salts, and
  • the compound of the present invention and pharmaceutically acceptable salt thereof can be produced by applying various known synthesis methods, making use of their characteristics based on the basic structures or kinds of substituents.
  • the desired compound can be obtained by removing the protecting group as occasion demands.
  • functional groups include amino group, hydroxyl group, carboxyl group and the like.
  • protecting groups include the protecting groups described in "Protective Groups in Organic Synthesis (2nd. Ed.)" edited by Greene and Wuts, and these groups are optionally used depending on the reaction conditions.
  • This production method is a method in which the compound of the present invention represented by the general formula (I) is obtained by reacting a compound (II) with a compound (III).
  • the leaving group L include halogen atoms and methylsulfanyl, 1H-benzotriazol-1-yloxy, methylsulfinyl, methanesulfonyl, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, and the like.
  • the reaction can be carried out from under cooling to under heating to reflux using the compounds (II) and (III) in equimolar amounts or in an excess amount of one of them, without solvent or in a solvent inert to the reaction such as aromatic hydrocarbons, e.g., benzene, toluene, xylene and the like; ethers, e.g., diethyl ether, tetrahydrofuran (THF), dioxane and the like; halogenated hydrocarbons, e.g., dichloromethane, 1,2-dichloroethane, chloroform and the like; N,N-dimethylformamide (DMF); N,N-dimethylacetamide (DMA); N-methylpyrrolidone; ethyl acetate; acetonitrile; and the like.
  • aromatic hydrocarbons e.g., benzene, toluene, xylene and the like
  • ethers
  • the reaction temperature can be optionally selected depending on the compounds. Depending on the compounds, it is advantageous in some cases to carry out the reaction in the presence of an organic base (preferably diisopropylethylamine, N-methylmorpholine, pyridine, or 4-(N,N-dimethylamino)pyridine) or a metal salt base (preferably sodium hydride, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, or potassium hydroxide).
  • an organic base preferably diisopropylethylamine, N-methylmorpholine, pyridine, or 4-(N,N-dimethylamino)pyridine
  • a metal salt base preferably sodium hydride, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, or potassium hydroxide.
  • This production method is a method in which the compound (I) of the invention is obtained by converting the nitrile group of a nitrile compound (IV) into a carboxamido group under various conditions.
  • the reaction can be carried out from at room temperature to under heating to reflux without solvent or in a solvent inert to the reaction such as aromatic hydrocarbons; ethers; halogenated hydrocarbons; alcohols, e.g., methanol, ethanol and the like; DMF; pyridine; water; dimethyl sulfoxide (DMSO); and the like, in the presence of a mineral acid, e.g., sulfuric acid, hydrochloric acid, hydrobromic acid or the like; an organic acid, e.g., formic acid, acetic acid or the like; or a base, e.g., sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, ammonia or the like. It is advantageous in some cases to carry out the reaction in the presence of hydrogen peroxide
  • a starting compound (II) can be produced by substitution reaction between a compound (VIII) and an aniline derivative (IX).
  • the reaction can be carried out under conditions similar to the above first production method.
  • the intermediate (VIII) can be produced by treating a carboxylic acid compound (VI) with ammonia in the presence of a condensing agent (e.g., dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC), 1,1'-carbonylbis-lH-imidazole (CDI), or the like) and, in some cases, an additive (e.g., N-hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole (HOBt), or the like).
  • a condensing agent e.g., dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC), 1,1'-carbonylbis
  • the intermediate (VI) can be produced by introducing a carboxylic acid into a compound (V) under various conditions.
  • the reaction can be carried out from at -78°C to under ice cooling in a solvent inert to the reaction such as ethers or hexane by converting the compound into an anion under a basic condition (e.g., n-butyllithium, sec-butyllithium, tert-butyllithium, 2,2,6,6-tetramethylpiperidine lithium salt (LiTMP), diisopropylamine lithium salt (LDA), or the like, or N,N,N',N'-tetramethylethylenediamine, hexamethylphosphoramide (HMPA), DMA, or the like may be added thereto in order to assist the reaction), and then adding dry ice or blowing carbon dioxide into the solution.
  • the reaction temperature can be selected optionally, depending on the compound.
  • the intermediate (VIII) can be also produced by hydrolyzing a nitrile compound (VII).
  • the conditions similar to those in the above second production method can be adopted as the reaction conditions.
  • L 2 represents a leaving group similar to the above L or R 6 or R 7
  • R 8 represents -aryl which may have substituent(s), -lower alkylene-aryl which may have substituent(s), or -aryl group which may have substituent(s)
  • W represents O or NR 1 .
  • Other symbols are defined as in the above
  • the starting compound (IVb) can be produced by reacting a compound (IVa) with a compound (XII).
  • the reaction can be carried out from under cooling to under heating in a solvent inert to the reaction such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, DMSO, pyridine, or the like. It is advantageous in some cases to carry out the reaction in the presence of a metal salt base, for the purpose of effecting smooth progress of the reaction.
  • the starting compound (IVa) can be produced by reacting a compound (XI) with the compound (III).
  • the conditions similar to those in the above first production method can be adopted.
  • the intermediate (XI) can be produced by the substitution reaction between a nitrile compound (X) and an aniline compound (IX).
  • the conditions similar to those in the above first production method can be adopted.
  • the compound wherein the substituent R 1 is an alkyl, -CO-lower alkyl, or -SO 2 -lower alkyl can be produced in the usual way using the compound wherein R 1 is H.
  • the introduction of an alkyl group can be carried out using an alkyl halide or an alkyl ester in a similar manner to the above first production method.
  • the introduction of the -CO-lower alkyl or -SO 2 -lower alkyl group can be carried out from under cooling to under heating in a solvent inert to the reaction such as halogenated hydrocarbons, ethers, DMF, or the like by an acid halide method, a mixed or symmetric acid anhydride method, an active ester method, a condensing agent (DCC, WSC, CDI, etc.) method, or the like. It is advantageous in some cases to carry out the reaction in the presence of a base, for the purpose of effecting smooth progress of the reaction.
  • reaction product obtained by each of the aforementioned production methods is isolated and purified as a free compound, a salt thereof or any of various types of solvate such as hydrate. Salts can be produced by the usual salt-forming treatment.
  • the isolation and purification are carried out by employing usual chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various chromatographic techniques, and the like.
  • optical isomers can be isolated in the usual way making use of a physicochemical difference among the isomers.
  • optical isomers can be separated by a general optical resolution method such as fractional crystallization or a chromatography.
  • an optical isomer can also be produced from an appropriate optically active starting compound.
  • the compound of the invention is useful as an active ingredient for pharmaceutical preparations. Particularly, since it has a Syk inhibitory activity, it is useful as an agent for preventing and treating the following diseases in which Syk takes part.
  • the diseases in which an allergic or inflammatory reaction becomes the main cause e.g., asthma, rhinitis, atopic dermatitis, contact dermatitis, nettle rash, food allergy, conjunctivitis, vernal conjunctivitis and the like
  • autoimmune diseases e.g., rheumatoid arthritis, systemic lupus erythematosus, psoriasis and the like
  • cancers and the like diseases in which immune reaction takes part (e.g., rejection at the time of organ transplantation, graft versus host disease and the like); diseases in which ADCC takes part (e.g., autoimmune hemolytic anemia, myasthenia gravis and the like); and diseases in which platelet agglutination takes part.
  • Human Syk gene in the form where a gene of FLAG tag consisting of 8 amino acid residues was linked to the 3'-end, was cloned using RT-PCR method from total RNA prepared from Jurkat cells.
  • the amplified cDNA was incorporated into a vector, pFASTBAC HT, contained in Baculovirus Expression System (GIBCO BRL Inc.).
  • the pFASTBAC HT is designed in such a manner that a His tag consisting of 6 histidine residues can be fused to the 5'-end of Syk.
  • This plasmid DNA was introduced into competent cells, DH10BAC, contained in the Baculovirus Expression System to prepare DNA of recombinant virus. Thereafter, the recombinant virus (culture supernatant) was obtained by transfection of the DNA of recombinant virus into Sf-9 cells (ATCC).
  • the Sf-9 cells infected with this recombinant virus were recovered and lysed using a lysis buffer containing 1% Triton X-100. After centrifugation of the soluble fraction, the supernatant was mixed with TALON resin (CLONTECH) to allow the His-tag fused protein of Syk to be adsorbed by the resin. After several times of washing of the resin, the His-tag fused protein of Syk was eluted with a buffer containing imidazole.
  • a peptide of 18 amino acid residues (MEELQDDYEDMMEENLEQ) (Sequence No.: 1) containing Tyr-8 of human erythrocyte Band 3 (Harrison, M. L. et al., J. Biol. Chem., 269: 955-959 (1994)) was synthesized using a peptide synthesizer. Using a biotinylation kit manufactured by Pierce, the N-terminal of the peptide in a resin-linked state was biotinylated, and purification was carried out using an HPLC.
  • SPA Scintillation Proximity Assay
  • Amersham making use of a phenomenon in which scintillation occurs when a molecule having a radioactivity is in the proximity of (linked to) the surface of plastic beads containing a scintillant included therein. These beads are coated in advance with streptoavidin to which the biotin moiety of substrate peptide is bound.
  • reaction-terminating solution 1% Triton X-100 (reaction-terminating solution) in an amount of 150 ⁇ l per well.
  • the plate was sealed, stirred, allowed to stand at room temperature for 15 minutes and then centrifuged at 1,500 rpm for 3 minutes to precipitate the SPA beads. Radioactivity of each well was measured using TOP COUNT (PACKARD), and the tyrosine phosphorylation activity by Syk was calculated.
  • the compounds of Examples of the invention exhibited an inhibitory activity of 0.05 ⁇ M or less as IC 50 value against Syk.
  • comparative compounds having a substituent in the carboxamido group 2-(2-aminoethylamino)-N-methyl-4-(3-trifluoromethylanilino)pyrimidine-5-carboxamide and 2-(2-aminoethylamino)-N,N-dimethyl-4-(3-trifluoromethylanilino)pyrimidine-5-carboxamide did not exhibit any inhibitory activity at 1 ⁇ M.
  • the compound of Examples 1, 2, 8, 10, and 11 exhibited an inhibitory activity of 0.1 ⁇ M or less as IC 50 value against the release of serotonin.
  • mice of 5 weeks age were sensitized by subcutaneously injecting 10 ⁇ l of anti-dinitrophenyl-IgE (DNP-IgE) (1,000 times dilution of a roughly purified product of ascites of Balb/c mouse to which a DNP-IgE producing hybridoma had been administered by intraperitoneal injection) into the right ear pinna while lightly anesthetizing with ether.
  • DNP-IgE anti-dinitrophenyl-IgE
  • 200 ⁇ l of 0.5% Evans blue solution containing 50 ⁇ g of DNP-conjugated bovine serum albumin was intravenously administered, and, after 30 minutes, each mouse was sacrificed through exsanguination to isolate both ears.
  • Each test compound or the vehicle alone as a control was administered subcutaneously 30 minutes before the antigen challenge or orally 2 hours before the challenge.
  • the dye in the tissues was extracted with formamide and colorimetrically determined at 620 nm. A value obtained by subtracting the dye content of the left ear from the dye content of the right ear was used as the amount of dye leaked into the tissues by the PCA reaction.
  • the PCA inhibition ratio by the test compound was calculated based on the following equation.
  • C amount of the dye leaked into the tissue at the time of the administration of the vehicle alone
  • X amount of the dye leaked into the tissue at the time of the administration of-the test compound.
  • Inhibition ratio (%) ⁇ C - X ⁇ x 100/C
  • the compound of the invention inhibits the release of inflammatory mediator and suppresses the anaphylaxis reaction, and especially has a Syk inhibitory activity.
  • the compound is useful as an agent for preventing and treating the diseases in which Syk takes part.
  • the pharmaceutical composition comprising one or two or more of the compounds represented by the general formula (I) or salts thereof as the active ingredient can be prepared by generally used methods using pharmaceutical carriers, fillers and the like which are generally used in this field.
  • Its administration form may be either oral administration by tablets, pills, capsules, granules, powders, liquids and the like, or parenteral administration by intravenous, intramuscular and the like injections, suppositories, eye drops, eye ointments, percutaneous liquids, ointments, percutaneous adhesive preparations, transmucosal liquids, transmucosal adhesive preparations, inhalants and the like.
  • the solid composition for use in the oral administration according to the invention is used in the form of tablets, powders, granules and the like.
  • one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, magnesium aluminate metasilicate.
  • the composition may contain other additives than the inert diluent, such as a lubricant, e.g., magnesium stearate or the like, a disintegrating agent, e.g., calcium cellulose glycolate or the like, a stabilizing agent, e.g., lactose or the like, and a solubilization-assisting agent, e.g., glutamic acid, aspartic acid or the like.
  • tablets or pills may be coated with a sugar or a film of gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like.
  • the liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like and contains a generally used inert diluent such as purified water or ethanol.
  • this composition may also contain auxiliary agents such as a solubilizing agent, a moistening agent, a suspending agent and the like, as well as sweeteners, flavors, aromatics and antiseptics.
  • the injections for parenteral administration include aseptic aqueous or non-aqueous solutions, suspensions and emulsions.
  • the aqueous solutions and suspensions include distilled water for injection or physiological saline.
  • propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol, polysorbate 80 (trade name) and the like may be used.
  • Such a composition may further contain auxiliary agents such as a tonicity, an antiseptic, a moisturizing agent, an emulsifying agent, a dispersing agent, a stabilizing agent (e.g., lactose) and a solubilization-assisting agent (e.g., glutamic acid or aspartic acid).
  • auxiliary agents such as a tonicity, an antiseptic, a moisturizing agent, an emulsifying agent, a dispersing agent, a stabilizing agent (e.g., lactose) and a solubilization-assisting agent (e.g., glutamic acid or aspartic acid).
  • auxiliary agents such as a tonicity, an antiseptic, a moisturizing agent, an emulsifying agent, a dispersing agent, a stabilizing agent (e.g., lactose) and a solubilization-assisting agent (e.g., glutamic acid or aspartic acid).
  • transmucosal preparations such as transnasal preparations are in the solid, liquid or semisolid form and can be produced by methods known per se. For example, they are formed into a solid, liquid or semisolid state by optionally adding known pH adjusting agents, antiseptics, thickeners, excipients and the like.
  • the transnasal preparations are administered using generally used sprayers, nasal drops containers, tubes, nasal cavity-inserting tools and the like.
  • the suitable daily dose is generally from about 0.001 to 100 mg/kg body weight, preferably from 0.1 to 10 mg/kg, which is administered in one portion or by dividing into two to four doses.
  • the suitable daily dose is from about 0.0001 to 10 mg/kg body weight, which is administered in one portion or by dividing into several doses.
  • a dose of from about 0.001 to 10 mg/kg body weight is administered once a day or by dividing into several doses. The dose is optionally determined in consideration of symptoms, age, sex and the like at individual case.
  • Example 2 The compounds of Examples 5 to 7 shown in Table 2 were produced in a similar manner to Example 1, the compounds of Examples 8 to 11 shown in Table 2 were produced in a similar manner to Example 2, the compounds of Examples 12 to 14 shown in Table 2 were produced in a similar manner to Example 3, and the compounds of Examples 15 and 16 were produced in a similar manner to Example 4, using corresponding raw materials. Structures and physicochemical data of the compounds of Examples 1 to 16 are shown in Table 2.
  • Rex Reference Example number, Ex: Example number, Cmpd: compound number, Ph: phenyl, Me: methyl, Et: ethyl, tBu: tert-butyl, Boc: tBuO-CO-, Bn: benzyl, Ac: acetyl, BCA: cis-2-(tert-butoxycarbonylamino)cyclohexylamino, PEA: (1'S,1R,2S)-2-(1'-phenylethylamino)cyclohexylamino, CCA: cis-2-aminocyclohexylamino, ACA: (1R,2S)-2aminocyclohexylamino.

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Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003078404A1 (fr) * 2002-03-15 2003-09-25 Novartis Ag Derives de pyrimidine
WO2005009443A1 (fr) * 2003-06-24 2005-02-03 Amgen Inc. Derives de 2-amino-4-hydroxy-5-pyrimidinocarboxamide et composes associes servant d'inhibiteurs de l'activation des lymphocytes t pour le traitement de maladies inflammatoires
WO2005016894A1 (fr) * 2003-08-15 2005-02-24 Novartis Ag 2, 4-pyrimidine diamines utiles dans le cadre du traitement de maladies neoplasiques, de troubles inflammatoires et de troubles du systeme immunitaire
EP1682147B1 (fr) * 2003-10-30 2009-10-07 Boehringer Ingelheim International GmbH Utilisation d'inhibiteurs de tyrosine-kinase pour traiter des processus inflammatoires
US7625903B2 (en) 2007-01-26 2009-12-01 Smithkline Beecham Corporation Anthranilamide inhibitors of Aurora kinase
WO2010097248A1 (fr) * 2009-01-13 2010-09-02 Glaxo Group Limited Dérivés de pyrimidine carboxamide comme inhibiteurs de la kinase syk
WO2010128659A1 (fr) * 2009-05-08 2010-11-11 アステラス製薬株式会社 Composé de carboxamide hétérocyclique diamino
WO2010144647A1 (fr) * 2009-06-12 2010-12-16 Bristol-Myers Squibb Company Composés de nicotinamide utiles en tant que modulateurs de kinases
US7964592B2 (en) 2003-03-14 2011-06-21 Novartis Ag 2,4-di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders
WO2011079051A1 (fr) 2009-12-23 2011-06-30 Takeda Pharmaceutical Company Limited Pyrrolidinones accolés en tant d'inhibiteurs de syk
WO2012061415A1 (fr) * 2010-11-01 2012-05-10 Portola Pharmaceuticals, Inc. Oxypyrimidines en tant que modulateurs de syk
WO2012061418A3 (fr) * 2010-11-01 2012-08-02 Portola Pharmaceuticals, Inc. Benzamides et nicotinamides en tant que modulateurs de syk
WO2012061428A3 (fr) * 2010-11-01 2012-10-11 Portola Pharmaceuticals, Inc. Nicotinamides en tant que modulateurs des jak kinases
WO2012145569A1 (fr) * 2011-04-22 2012-10-26 Signal Pharmaceuticals, Llc Diaminocarboxamidepyrimidines et diaminocarbonitrilepyrimidines substituées, compositions de celles-ci et procédés de traitement à l'aide de celles-ci
WO2012177714A1 (fr) 2011-06-22 2012-12-27 Takeda Pharmaceutical Company Limited Dérivés de 6-aza-isoindolin-1-one substitués
EP2589592A1 (fr) * 2010-06-30 2013-05-08 FUJIFILM Corporation Nouveaux dérivés de nicotinamide et leurs sels
WO2013104573A1 (fr) * 2012-01-10 2013-07-18 F. Hoffmann-La Roche Ag Composés de pyridazinamide et leur utilisation en tant qu'inhibiteurs de syk
WO2013171690A1 (fr) * 2012-05-16 2013-11-21 Novartis Ag Dérivés hétéroaryles monocycliques de cycloalkyldiamine
EP2130541A3 (fr) * 2002-07-29 2013-12-18 Rigel Pharmaceuticals, Inc. Procédés de traitement ou de prévention des maladies auto-immunes avec des composants de pyrimidinediamine 2,4
WO2013192049A2 (fr) 2012-06-22 2013-12-27 Portola Pharmaceuticals, Inc. Inhibiteurs de 1,2,4-triazine-6-carboxamide kinase
WO2014045029A1 (fr) * 2012-09-18 2014-03-27 Ziarco Pharma Ltd 2-(2-aminocyclohexyl)aminopyrimidino-5-carboxamides utilisés comme inhibiteurs de la spleen tyrosine kinase (syk)
WO2014074661A1 (fr) * 2012-11-08 2014-05-15 Bristol-Myers Squibb Company Composés hétérocycliques substitués par amide, utiles comme modulateurs d'il-12, il-23 et/ou de réponses à l'ifnα
WO2014111031A1 (fr) * 2013-01-17 2014-07-24 四川恒康发展有限责任公司 Composé triazine, sel pharmaceutique, isomère, ou hydrate de celui-ci, et composition pharmaceutique de celui-ci
CN104066431A (zh) * 2011-11-23 2014-09-24 波托拉医药品公司 吡嗪激酶抑制剂
US8952027B2 (en) 2008-04-16 2015-02-10 Portola Pharmaceuticals, Inc. Inhibitors of syk and JAK protein kinases
EP2763976A4 (fr) * 2011-10-05 2015-03-04 Merck Sharp & Dohme Inhibiteurs de tyrosine kinase de la rate (syk) contenant un 2-pyridyl carboxamide
EP2763975A4 (fr) * 2011-10-05 2015-03-11 Merck Sharp & Dohme Inhibiteurs de tyrosine kinase de la rate (syk) contenant un 3-pyridyl carboxamide
CN104602681A (zh) * 2012-06-22 2015-05-06 博尔托拉制药公司 取代的吡啶酰胺激酶抑制剂
EP2763974A4 (fr) * 2011-10-05 2015-06-03 Merck Sharp & Dohme Inhibiteurs de tyrosine kinase de la rate (syk) contenant un phényl carboxamide
US9051310B2 (en) 2011-12-28 2015-06-09 Fujifilm Corporation Nicotinamide derivative or salt thereof
EP2773207A4 (fr) * 2011-10-31 2015-07-01 Merck Sharp & Dohme Aminopyrimidinones en tant qu'inhibiteurs de kinases associées au récepteur de l'interleukine
WO2015061247A3 (fr) * 2013-10-21 2015-07-23 Merck Patent Gmbh Composés hétéroaryle servant d'inhibiteurs de la btk et leurs utilisations
EP2909174A1 (fr) * 2012-10-19 2015-08-26 F. Hoffmann-La Roche AG Inhibiteurs de syk
US9145414B2 (en) 2011-09-30 2015-09-29 Taiho Pharmaceutical Co., Ltd. 1,2,4-triazine-6-carboxamide derivative
US9365524B2 (en) 2014-01-30 2016-06-14 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US9513297B2 (en) 2014-12-16 2016-12-06 Signal Pharmaceuticals, Llc Methods for measurement of inhibition of c-Jun N-terminal kinase in skin
US9796685B2 (en) 2014-12-16 2017-10-24 Signal Pharmaceuticals, Llc Formulations of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-Methylcyclohexylamino)-pyrimidine-5-carboxamide
US9868729B2 (en) 2008-04-16 2018-01-16 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US10252981B2 (en) 2015-07-24 2019-04-09 Celgene Corporation Methods of synthesis of (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride and intermediates useful therein
WO2019076817A1 (fr) 2017-10-19 2019-04-25 Bayer Animal Health Gmbh Utilisation de pyrrolidones hétéroaromatiques fusionnées pour le traitement et la prévention de maladies chez des animaux
US10689351B2 (en) 2015-01-29 2020-06-23 Signal Pharmaceuticals, Llc Isotopologues of 2-(tert butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide

Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040253178A1 (en) * 2002-12-20 2004-12-16 Shane Atwell Crystals and structures of spleen tyrosine kinase SYKKD
EP1590334B1 (fr) 2003-01-30 2009-08-19 Boehringer Ingelheim Pharmaceuticals Inc. Derives de 2,4-diaminopyrimidine utiles en tant qu'inhibiteurs de l'enzyme pkc-theta
US7601714B2 (en) 2004-07-08 2009-10-13 Boehringer Ingelheim Pharmaceuticals, Inc. Pyrimidine derivatives useful as inhibitors of PKC-theta
RS53588B1 (en) 2006-12-08 2015-02-27 Irm Llc COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
RU2009128982A (ru) 2006-12-28 2011-02-10 Тайсо Фармасьютикал Ко., Лтд. (Jp) Пиразолопиримидиновые соединения
SG2014015085A (en) * 2008-04-16 2014-06-27 Portola Pharm Inc 2,6-diamino-pyrimidin-5-yl-carboxamides as syk or jak kinases inhibitors
JP5487692B2 (ja) 2009-04-10 2014-05-07 国立大学法人京都大学 複素環骨格を有する化合物および該化合物を不斉触媒として用いる光学活性化合物の製造方法
JP2014005206A (ja) * 2010-10-22 2014-01-16 Astellas Pharma Inc アリールアミノヘテロ環カルボキサミド化合物
RU2013154412A (ru) 2011-05-10 2015-06-20 Мерк Шарп И Доум Корп. Аминопиримидины в качестве ингибиторов syc
US9145391B2 (en) 2011-05-10 2015-09-29 Merck Sharp & Dohme Corp. Bipyridylaminopyridines as Syk inhibitors
JP2014513687A (ja) 2011-05-10 2014-06-05 メルク・シャープ・アンド・ドーム・コーポレーション Ｓｙｋ阻害薬としてのピリジルアミノピリジン
EP2863913B1 (fr) 2012-06-20 2018-09-12 Merck Sharp & Dohme Corp. Analogues d'imidazolyle en tant qu'inhibiteurs de syk
EP2863916B1 (fr) 2012-06-22 2018-07-18 Merck Sharp & Dohme Corp. Inhibiteurs à pyridine substituée de la tyrosine kinase de la rate (syk)
US9416111B2 (en) 2012-06-22 2016-08-16 Merck Sharp & Dohme Corp. Substituted diazine and triazine spleen tyrosine kinease (Syk) inhibitors
US9353066B2 (en) 2012-08-20 2016-05-31 Merck Sharp & Dohme Corp. Substituted phenyl-Spleen Tyrosine Kinase (Syk) inhibitors
WO2014048065A1 (fr) 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Dérivés triazolyle en tant qu'inhibiteurs de la syk
US9624210B2 (en) 2012-12-12 2017-04-18 Merck Sharp & Dohme Corp. Amino-pyrimidine-containing spleen tyrosine kinase (Syk) inhibitors
US9598405B2 (en) 2012-12-21 2017-03-21 Merck Sharp & Dohme Corp. Thiazole-substituted aminopyridines as spleen tyrosine kinase inhibitors
JP2016113366A (ja) * 2013-03-29 2016-06-23 大鵬薬品工業株式会社 アセトアミド基を有する１，２，４−トリアジン−６−カルボキサミド誘導体
EP2988744A4 (fr) 2013-04-26 2016-11-02 Merck Sharp & Dohme Composés aminohétéroaryle à substitution thiazole inhibiteurs de tyrosine kinase splénique
EP2988749B1 (fr) 2013-04-26 2019-08-14 Merck Sharp & Dohme Corp. Aminopyrimidines substituées par thiazole utilisées en tant qu'inhibiteurs de tyrosine kinase splénique
US9382246B2 (en) 2013-12-05 2016-07-05 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase
US9783531B2 (en) 2013-12-20 2017-10-10 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
EP3083559B1 (fr) 2013-12-20 2021-03-10 Merck Sharp & Dohme Corp. Composés aminohétéroaryles à substitution thiazole utilisés comme inhibiteurs de la tyrosine kinase splénique
US9670196B2 (en) 2013-12-20 2017-06-06 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as Spleen Tyrosine Kinase inhibitors
WO2015123453A1 (fr) * 2014-02-14 2015-08-20 Portola Pharmaceuticals, Inc. Composés de pyridazine en tant qu'inhibiteurs de jak
WO2015138273A1 (fr) 2014-03-13 2015-09-17 Merck Sharp & Dohme Corp. Composés 2-pyrazine carboxamide utiles comme inhibiteurs de la tyrosine kinase splénique
CA2987054A1 (fr) * 2015-06-02 2016-12-08 Pharmacyclics Llc Inhibiteurs de la tyrosine kinase de bruton
EP3601268B1 (fr) * 2017-03-30 2021-03-17 Bristol-Myers Squibb Company Procédé de préparation de 6-(cyclopropaneamido)-4-((2-méthoxy-3-(1-méthyl-1h-1,2,4-triazol-3-yl) phényl)amino)-n-(méthyl-d3)pyridazine-3-carboxamide
MX2021009863A (es) 2019-03-21 2021-11-12 Onxeo Una molecula dbait en combinacion con inhibidor de quinasa para el tratamiento del cancer.
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WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997019065A1 (fr) * 1995-11-20 1997-05-29 Celltech Therapeutics Limited 2-anilinopyrimidines substituees utiles en tant qu'inhibiteurs de proteine kinase
WO1998018782A1 (fr) * 1996-10-28 1998-05-07 Celltech Therapeutics Limited Derives de 2-pyrimidineamine et procedes de preparation
WO1998041512A1 (fr) * 1997-03-14 1998-09-24 Celltech Therapeutics Limited 2-anilinopyrimidines substituees utilisees en tant qu'inhibiteurs de la proteine kinase

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1405308A (en) 1972-12-13 1975-09-10 Basf Ag Amino-pytidines as coupling components for azo dyes
US4442095A (en) * 1982-12-27 1984-04-10 Merck & Co., Inc. N-[(5-Halo-2,6-(substituted)pyrazinyl)methylene]amine antimicrobial compounds, compositions and use
EP0600832A1 (fr) * 1992-11-27 1994-06-08 Ciba-Geigy Ag Dérivés de diamino acid benzoique et diamino acid phthalique et leur application à titre des inhibiteurs de protéine kinase
EP0738144A4 (fr) * 1993-12-30 1999-06-30 Smithkline Beecham Corp Hexanamides de phenylmethyle et leur utilisation
JP4135318B2 (ja) 1997-12-15 2008-08-20 アステラス製薬株式会社 新規なピリミジン−５−カルボキサミド誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997019065A1 (fr) * 1995-11-20 1997-05-29 Celltech Therapeutics Limited 2-anilinopyrimidines substituees utiles en tant qu'inhibiteurs de proteine kinase
WO1998018782A1 (fr) * 1996-10-28 1998-05-07 Celltech Therapeutics Limited Derives de 2-pyrimidineamine et procedes de preparation
WO1998041512A1 (fr) * 1997-03-14 1998-09-24 Celltech Therapeutics Limited 2-anilinopyrimidines substituees utilisees en tant qu'inhibiteurs de la proteine kinase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO0075113A1 *

Cited By (133)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003078404A1 (fr) * 2002-03-15 2003-09-25 Novartis Ag Derives de pyrimidine
EP2308855A1 (fr) * 2002-03-15 2011-04-13 Novartis AG Dérivés de 2,4-Diaminopyrimidine
US7943627B2 (en) 2002-03-15 2011-05-17 Novartis Ag 2,4-diaminopyrimidine derivatives
US8431589B2 (en) 2002-03-15 2013-04-30 Novartis Ag 2,4-diaminopyrimidine derivatives
EP2130541A3 (fr) * 2002-07-29 2013-12-18 Rigel Pharmaceuticals, Inc. Procédés de traitement ou de prévention des maladies auto-immunes avec des composants de pyrimidinediamine 2,4
US7964592B2 (en) 2003-03-14 2011-06-21 Novartis Ag 2,4-di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders
US8263590B2 (en) 2003-03-14 2012-09-11 Carlos Garcia-Echeverria Pyrimidine derivatives
US7504396B2 (en) 2003-06-24 2009-03-17 Amgen Inc. Substituted heterocyclic compounds and methods of use
WO2005009443A1 (fr) * 2003-06-24 2005-02-03 Amgen Inc. Derives de 2-amino-4-hydroxy-5-pyrimidinocarboxamide et composes associes servant d'inhibiteurs de l'activation des lymphocytes t pour le traitement de maladies inflammatoires
WO2005016894A1 (fr) * 2003-08-15 2005-02-24 Novartis Ag 2, 4-pyrimidine diamines utiles dans le cadre du traitement de maladies neoplasiques, de troubles inflammatoires et de troubles du systeme immunitaire
EP1682147B1 (fr) * 2003-10-30 2009-10-07 Boehringer Ingelheim International GmbH Utilisation d'inhibiteurs de tyrosine-kinase pour traiter des processus inflammatoires
US7625903B2 (en) 2007-01-26 2009-12-01 Smithkline Beecham Corporation Anthranilamide inhibitors of Aurora kinase
US8952027B2 (en) 2008-04-16 2015-02-10 Portola Pharmaceuticals, Inc. Inhibitors of syk and JAK protein kinases
US10533001B2 (en) 2008-04-16 2020-01-14 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US11414410B2 (en) 2008-04-16 2022-08-16 Alexion Pharmaceuticals, Inc. Inhibitors of protein kinases
US9868729B2 (en) 2008-04-16 2018-01-16 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US9579320B2 (en) 2008-04-16 2017-02-28 Portola Pharmaceuticals, Inc. Inhibitors of syk and JAK protein kinases
WO2010097248A1 (fr) * 2009-01-13 2010-09-02 Glaxo Group Limited Dérivés de pyrimidine carboxamide comme inhibiteurs de la kinase syk
CN102348707A (zh) * 2009-01-13 2012-02-08 葛兰素集团有限公司 作为syk激酶抑制剂的嘧啶甲酰胺衍生物
US8470835B2 (en) 2009-01-13 2013-06-25 Glaxo Group Limited Pyrimidinecarboxamide derivatives as inhibitors of Syk kinase
CN102421761B (zh) * 2009-05-08 2014-06-18 安斯泰来制药株式会社 二氨基杂环甲酰胺化合物
US9487491B2 (en) 2009-05-08 2016-11-08 Astellas Pharma Inc. Diamino heterocyclic carboxamide compound
TWI484961B (zh) * 2009-05-08 2015-05-21 Astellas Pharma Inc Diamine heterocyclic methyl ester compounds
US8969336B2 (en) 2009-05-08 2015-03-03 Astellas Pharma Inc. Diamino heterocyclic carboxamide compound
WO2010128659A1 (fr) * 2009-05-08 2010-11-11 アステラス製薬株式会社 Composé de carboxamide hétérocyclique diamino
CN102421761A (zh) * 2009-05-08 2012-04-18 安斯泰来制药株式会社 二氨基杂环甲酰胺化合物
WO2010144647A1 (fr) * 2009-06-12 2010-12-16 Bristol-Myers Squibb Company Composés de nicotinamide utiles en tant que modulateurs de kinases
CN102458402A (zh) * 2009-06-12 2012-05-16 百时美施贵宝公司 用作激酶调节剂的烟酰胺化合物
CN102458402B (zh) * 2009-06-12 2013-10-02 百时美施贵宝公司 用作激酶调节剂的烟酰胺化合物
WO2011079051A1 (fr) 2009-12-23 2011-06-30 Takeda Pharmaceutical Company Limited Pyrrolidinones accolés en tant d'inhibiteurs de syk
EP2902392A1 (fr) 2009-12-23 2015-08-05 Takeda Pharmaceutical Company Limited Pyrrolidinones hétéroaromatiques fusionnés comme inhibiteurs de la syk
EP3825316A1 (fr) 2009-12-23 2021-05-26 Takeda Pharmaceutical Company Limited Pyrrolidinones hétéroaromatiques fusionnés comme inhibiteurs du syk
US9108970B2 (en) 2009-12-23 2015-08-18 Takeda Pharmaceutical Company Limited Fused heteroaromatic pyrrolidinones
US8440689B2 (en) 2009-12-23 2013-05-14 Takeda Pharmaceutical Company Limited Fused heteroaromatic pyrrolidinones
EP3489236A1 (fr) 2009-12-23 2019-05-29 Takeda Pharmaceutical Company Limited Procédé de préparation de pyrrolidinones hétéroaromatiques fusionnés
US9181255B2 (en) 2009-12-23 2015-11-10 Takeda Pharmaceutical Company Limited Fused heteroaromatic pyrrolidinones as SYK inhibitors
EP2589592A1 (fr) * 2010-06-30 2013-05-08 FUJIFILM Corporation Nouveaux dérivés de nicotinamide et leurs sels
US8895585B2 (en) 2010-06-30 2014-11-25 Fujifilm Corporation Nicotinamide derivative or salt thereof
EP2589592A4 (fr) * 2010-06-30 2014-01-01 Fujifilm Corp Nouveaux dérivés de nicotinamide et leurs sels
RU2560163C2 (ru) * 2010-06-30 2015-08-20 Фуджифилм Корпорэйшн Новое производное никотинамида или его соль
EP3176154A1 (fr) * 2010-11-01 2017-06-07 Portola Pharmaceuticals, Inc. Benzamides et nicotinamides en tant que modulateurs de syk
US9359375B2 (en) 2010-11-01 2016-06-07 Portola Pharmaceuticals, Inc. Benzamides and nicotinamides as Syk modulators
CN103282352B (zh) * 2010-11-01 2016-08-10 波托拉医药品公司 作为syk调节剂的苯甲酰胺类和烟酰胺类
WO2012061418A3 (fr) * 2010-11-01 2012-08-02 Portola Pharmaceuticals, Inc. Benzamides et nicotinamides en tant que modulateurs de syk
AU2011323484B2 (en) * 2010-11-01 2016-10-06 Portola Pharmaceuticals, Inc. Benzamides and nicotinamides as Syk modulators
WO2012061415A1 (fr) * 2010-11-01 2012-05-10 Portola Pharmaceuticals, Inc. Oxypyrimidines en tant que modulateurs de syk
US8846928B2 (en) 2010-11-01 2014-09-30 Portola Pharmaceuticals, Inc. Benzamides and nicotinamides as Syk modulators
CN103282352A (zh) * 2010-11-01 2013-09-04 波托拉医药品公司 作为syk调节剂的苯甲酰胺类和烟酰胺类
US9902688B2 (en) 2010-11-01 2018-02-27 Portola Pharmaceuticals, Inc. Benzamides and nicotinamides as Syk modulators
WO2012061428A3 (fr) * 2010-11-01 2012-10-11 Portola Pharmaceuticals, Inc. Nicotinamides en tant que modulateurs des jak kinases
US9102625B2 (en) 2010-11-01 2015-08-11 Portola Pharmaceuticals, Inc. Nicotinamides as JAK kinase modulators
US9139534B2 (en) 2011-04-22 2015-09-22 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
CN103492370B (zh) * 2011-04-22 2016-10-26 西格诺药品有限公司 取代的二氨基甲酰胺和二氨基甲腈嘧啶，其组合物，和用其治疗的方法
WO2012145569A1 (fr) * 2011-04-22 2012-10-26 Signal Pharmaceuticals, Llc Diaminocarboxamidepyrimidines et diaminocarbonitrilepyrimidines substituées, compositions de celles-ci et procédés de traitement à l'aide de celles-ci
US10919865B2 (en) 2011-04-22 2021-02-16 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
CN111499580A (zh) * 2011-04-22 2020-08-07 西格诺药品有限公司 取代的二氨基甲酰胺和二氨基甲腈嘧啶，其组合物，和用其治疗的方法
US10040770B2 (en) 2011-04-22 2018-08-07 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US11325890B2 (en) 2011-04-22 2022-05-10 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US12129237B2 (en) 2011-04-22 2024-10-29 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US10266500B2 (en) 2011-04-22 2019-04-23 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US9701643B2 (en) 2011-04-22 2017-07-11 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
RU2697712C2 (ru) * 2011-04-22 2019-08-19 СИГНАЛ ФАРМАСЬЮТИКАЛЗ, ЭлЭлСи Замещенные диаминокарбоксамидные и диаминокарбонитрильные производные пиримидинов, их композиции и способы лечения с их помощью
EP4328223A3 (fr) * 2011-04-22 2024-11-06 Signal Pharmaceuticals, LLC Diaminocarboxamidepyrimidines et diaminocarbonitrilepyrimidines substituées, compositions de celles-ci et procédés de traitement à l'aide de celles-ci
CN103492370A (zh) * 2011-04-22 2014-01-01 西格诺药品有限公司 取代的二氨基甲酰胺和二氨基甲腈嘧啶，其组合物，和用其治疗的方法
WO2012177714A1 (fr) 2011-06-22 2012-12-27 Takeda Pharmaceutical Company Limited Dérivés de 6-aza-isoindolin-1-one substitués
US9663514B2 (en) 2011-06-22 2017-05-30 Takeda Pharmaceutical Company Limited Substituted 6-aza-isoindolin-1-one derivatives
US9056873B2 (en) 2011-06-22 2015-06-16 Takeda Pharmaceutical Company Limited Substituted 6-aza-isoindolin-1-one derivatives
US9145414B2 (en) 2011-09-30 2015-09-29 Taiho Pharmaceutical Co., Ltd. 1,2,4-triazine-6-carboxamide derivative
EP2763976A4 (fr) * 2011-10-05 2015-03-04 Merck Sharp & Dohme Inhibiteurs de tyrosine kinase de la rate (syk) contenant un 2-pyridyl carboxamide
EP2763975A4 (fr) * 2011-10-05 2015-03-11 Merck Sharp & Dohme Inhibiteurs de tyrosine kinase de la rate (syk) contenant un 3-pyridyl carboxamide
EP2763974A4 (fr) * 2011-10-05 2015-06-03 Merck Sharp & Dohme Inhibiteurs de tyrosine kinase de la rate (syk) contenant un phényl carboxamide
US9221809B2 (en) 2011-10-31 2015-12-29 Merck Sharp & Dohme Corp. Aminopyrimidinones as interleukin receptor-associated kinase inhibitors
EP2773207A4 (fr) * 2011-10-31 2015-07-01 Merck Sharp & Dohme Aminopyrimidinones en tant qu'inhibiteurs de kinases associées au récepteur de l'interleukine
CN104066431A (zh) * 2011-11-23 2014-09-24 波托拉医药品公司 吡嗪激酶抑制剂
US9359308B2 (en) 2011-11-23 2016-06-07 Portola Pharmaceuticals, Inc. Pyrazine kinase inhibitors
CN104066431B (zh) * 2011-11-23 2017-03-08 波托拉医药品公司 吡嗪激酶抑制剂
US9051310B2 (en) 2011-12-28 2015-06-09 Fujifilm Corporation Nicotinamide derivative or salt thereof
CN104159891B (zh) * 2012-01-10 2016-09-07 霍夫曼-拉罗奇有限公司 哒嗪酰胺化合物和它们作为syk 抑制剂的用途
CN104159891A (zh) * 2012-01-10 2014-11-19 霍夫曼-拉罗奇有限公司 哒嗪酰胺化合物和它们作为syk 抑制剂的用途
US8901124B2 (en) 2012-01-10 2014-12-02 Hoffmann-La Roche Inc. Pyridazine amide compounds useful as SYK inhibitors
TWI557115B (zh) * 2012-01-10 2016-11-11 赫孚孟拉羅股份公司 嗒醯胺化合物
WO2013104573A1 (fr) * 2012-01-10 2013-07-18 F. Hoffmann-La Roche Ag Composés de pyridazinamide et leur utilisation en tant qu'inhibiteurs de syk
RU2627661C2 (ru) * 2012-01-10 2017-08-09 Ф. Хоффманн-Ля Рош Аг Соединения пиридазинамида и их применение в качестве ингибиторов тирозинкиназы селезенки (syk)
WO2013171690A1 (fr) * 2012-05-16 2013-11-21 Novartis Ag Dérivés hétéroaryles monocycliques de cycloalkyldiamine
CN104302641A (zh) * 2012-05-16 2015-01-21 诺华股份有限公司 单环杂芳基环烷基二胺衍生物
EP2863748A4 (fr) * 2012-06-22 2015-12-09 Portola Pharm Inc Inhibiteurs de 1,2,4-triazine-6-carboxamide kinase
AU2013277476B2 (en) * 2012-06-22 2016-12-15 Alexion Pharmaceuticals, Inc. 1,2,4-triazine-6-carboxamide kinase inhibitors
WO2013192049A2 (fr) 2012-06-22 2013-12-27 Portola Pharmaceuticals, Inc. Inhibiteurs de 1,2,4-triazine-6-carboxamide kinase
EP2863905A4 (fr) * 2012-06-22 2015-12-16 Portola Pharm Inc Inhibiteurs substitués de picolinamide kinase
CN104602681A (zh) * 2012-06-22 2015-05-06 博尔托拉制药公司 取代的吡啶酰胺激酶抑制剂
US10065964B2 (en) 2012-09-18 2018-09-04 Ziarco Pharma Ltd. Pyrimidine-5-carboxamides as spleen tyrosine kinase inhibitors
US9533989B2 (en) 2012-09-18 2017-01-03 Ziarco Pharma Ltd. Substituted pyrimidine-5-carboxamides as spleen tyrosine kinase inhibitors
WO2014045029A1 (fr) * 2012-09-18 2014-03-27 Ziarco Pharma Ltd 2-(2-aminocyclohexyl)aminopyrimidino-5-carboxamides utilisés comme inhibiteurs de la spleen tyrosine kinase (syk)
EP2909174A1 (fr) * 2012-10-19 2015-08-26 F. Hoffmann-La Roche AG Inhibiteurs de syk
CN104884454B (zh) * 2012-11-08 2017-11-28 百时美施贵宝公司 用作IL‑12、IL‑23和/或IFNα应答调节剂的酰胺取代的杂环化合物
KR20150081339A (ko) * 2012-11-08 2015-07-13 브리스톨-마이어스 스큅 컴퍼니 ＩＬ-12, ＩＬ-23 및/또는 ＩＦＮα 반응의 조절제로서 유용한 아미드-치환된 헤테로시클릭 화합물
US10000480B2 (en) 2012-11-08 2018-06-19 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFN alpha responses
WO2014074661A1 (fr) * 2012-11-08 2014-05-15 Bristol-Myers Squibb Company Composés hétérocycliques substitués par amide, utiles comme modulateurs d'il-12, il-23 et/ou de réponses à l'ifnα
EA028814B1 (ru) * 2012-11-08 2018-01-31 Бристол-Майерс Сквибб Компани АМИДЗАМЕЩЕННЫЕ ГЕТЕРОЦИКЛИЧЕСКИЕ СОЕДИНЕНИЯ, ПРИМЕНИМЫЕ В КАЧЕСТВЕ МОДУЛЯТОРОВ ОТВЕТОВ, ОПОСРЕДУЕМЫХ IL-12, IL-23 И/ИЛИ IFNα
US11021475B2 (en) 2012-11-08 2021-06-01 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFN alpha responses
EP4071144A1 (fr) * 2012-11-08 2022-10-12 Bristol-Myers Squibb Company Composés hétérocycliques substitués par des groupements amides utiles en tant que modulateurs d'il-12, il-23 et/ou de réponses ifn alpha
US9505748B2 (en) 2012-11-08 2016-11-29 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFNα responses
AU2020203967B2 (en) * 2012-11-08 2020-10-22 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
US10526321B2 (en) 2012-11-08 2020-01-07 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFN alpha responses
USRE47929E1 (en) 2012-11-08 2020-04-07 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFNα responses
CN104884454A (zh) * 2012-11-08 2015-09-02 百时美施贵宝公司 用作IL-12、IL-23和/或IFNα应答调节剂的酰胺取代的杂环化合物
EP3495358A1 (fr) * 2012-11-08 2019-06-12 Bristol-Myers Squibb Company Composés hétérocycliques substitués par des groupements amides utiles en tant que modulateurs d'il-12, il-23 et/ou de réponses ifn alpha
AU2018267545B2 (en) * 2012-11-08 2020-04-02 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
AU2013341186B2 (en) * 2012-11-08 2017-03-30 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFN alpha responses
US20170022192A1 (en) * 2012-11-08 2017-01-26 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
CN104870437A (zh) * 2013-01-17 2015-08-26 四川恒康发展有限责任公司 三嗪化合物、其药用盐、异构体或水合物及其药物组合物
WO2014111031A1 (fr) * 2013-01-17 2014-07-24 四川恒康发展有限责任公司 Composé triazine, sel pharmaceutique, isomère, ou hydrate de celui-ci, et composition pharmaceutique de celui-ci
WO2015061247A3 (fr) * 2013-10-21 2015-07-23 Merck Patent Gmbh Composés hétéroaryle servant d'inhibiteurs de la btk et leurs utilisations
US10329270B2 (en) 2013-10-21 2019-06-25 Merck Patent Gmbh Heteroaryl compounds as BTK inhibitors and uses thereof
US10517873B2 (en) 2014-01-30 2019-12-31 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US9365524B2 (en) 2014-01-30 2016-06-14 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US9814713B2 (en) 2014-01-30 2017-11-14 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US10226461B2 (en) 2014-01-30 2019-03-12 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US11241430B2 (en) 2014-01-30 2022-02-08 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US10197579B2 (en) 2014-12-16 2019-02-05 Signal Pharmaceuticals, Llc Methods for measurement of inhibition of c-Jun N-terminal kinase in skin
US9796685B2 (en) 2014-12-16 2017-10-24 Signal Pharmaceuticals, Llc Formulations of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-Methylcyclohexylamino)-pyrimidine-5-carboxamide
US9513297B2 (en) 2014-12-16 2016-12-06 Signal Pharmaceuticals, Llc Methods for measurement of inhibition of c-Jun N-terminal kinase in skin
US10131639B2 (en) 2014-12-16 2018-11-20 Signal Pharmaceuticals, Llc Formulations of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4methylcyclohexylamino)-pyrimidine-5-carboxamide
US10590089B2 (en) 2014-12-16 2020-03-17 Signal Pharmaceuticals, Llc Formulations of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide
US10689351B2 (en) 2015-01-29 2020-06-23 Signal Pharmaceuticals, Llc Isotopologues of 2-(tert butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide
US11492332B2 (en) 2015-01-29 2022-11-08 Signal Pharmaceuticals, Llc Isotopologues of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide
US10975039B2 (en) 2015-01-29 2021-04-13 Signal Pharmaceuticals, Llc Isotopologues of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide
US10252981B2 (en) 2015-07-24 2019-04-09 Celgene Corporation Methods of synthesis of (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride and intermediates useful therein
US11192847B2 (en) 2015-07-24 2021-12-07 Celgene Corporation Methods of synthesis of (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride and intermediates useful therein
US11780801B2 (en) 2015-07-24 2023-10-10 Celgene Corporation Methods of synthesis of (1R,2R,5R)-5-amino-2-methyl-cyclohexanol hydrochloride and intermediates useful therein
US10774033B2 (en) 2015-07-24 2020-09-15 Celgene Corporation Methods of synthesis of (1R, 2R, 5R)-5-amino-2-methylcyclohexanol hydrochloride and intermediates useful therein
US11077111B2 (en) 2017-10-19 2021-08-03 Bayer Animal Health Gmbh Use of fused heteroaromatic pyrrolidones for treatment and prevention of diseases in animals
WO2019076817A1 (fr) 2017-10-19 2019-04-25 Bayer Animal Health Gmbh Utilisation de pyrrolidones hétéroaromatiques fusionnées pour le traitement et la prévention de maladies chez des animaux

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ATE288420T1 (de) 2005-02-15
ES2237430T3 (es) 2005-08-01
DE60017898T2 (de) 2006-01-12
US6797706B1 (en) 2004-09-28
WO2000075113A1 (fr) 2000-12-14
AU5107900A (en) 2000-12-28
EP1184376B1 (fr) 2005-02-02

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